Synergistic Effects of Nanosecond Pulsed Electric Fields Combined with Low Concentration of Gemcitabine on Human Oral Squamous Cell Carcinoma In Vitro

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The PI3K/mTOR/AKT pathway is activated in most melanomas, but mTOR inhibitors used singly have limited activity against advanced melanomas. The application of nanosecond pulsed electric fields (nsPEFs) is a promising cancer therapy approach. In this study, we evaluated the synergistic anti-tumour efficacy of the mTOR inhibitor everolimus in conjunction with nsPEFs against melanoma. The combined treatment of nsPEFs and everolimus gradually decreased cell growth concurrent with nsPEF intensity. nsPEFs alone or combined with everolimus could promote melanoma cell apoptosis, accompanied with a loss in cellular mitochondrial membrane potential and an increase in Ca2+ levels. In vivo experiments showed that a combination of the mTOR inhibitor everolimus and nsPEFs improved the inhibitory effect, and all skin lesions caused by nsPEFs healed in 1 week without any observed adverse effect. Combination treatment induced caspase-dependent apoptosis through the upregulation of the pro-apoptotic factor Bax and downregulation of the anti-apoptotic factor Bcl-2. Everolimus and nsPEFs synergistically inhibited angiogenesis by decreasing the expression of vascular endothelial growth factor (VEGF), VEGF receptor (VEGFR), and CD34. Our findings indicate that nsPEFs in combination with an mTOR inhibitor can be used as a potential treatment approach for advanced melanoma.

mentioning

confidence: 80%

Nanosecond Pulsed Electric Fields Enhance the Anti-tumour Effects of the mTOR Inhibitor Everolimus against Melanoma

Dai

Kong

et al. 2017

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“…The nsPEF generator was applied as previously described54. Digital phosphor oscilloscope (DPO4054, Tektronix) with a probe (P6015A, Tektronix) was utilized to monitor the voltage waveform.…”

Section: Methodsmentioning

confidence: 99%

Nanosecond Pulsed Electric Fields (nsPEFs) Regulate Phenotypes of Chondrocytes through Wnt/β-catenin Signaling Pathway

Zhang

Guo

et al. 2014

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Nanosecond pulsed electric fields (nsPEFs) characterized by high voltage, low energy and non-thermal effects, have been broadly investigated as a potential tumor therapy; however, little is known about their effects on somatic cells. In this current study, we evaluated effects of nsPEFs on the phenotype of chondrocytes (morphology, glycosaminoglycan (GAG) content, proliferation and gene expression) and explored the mechanisms involved. Our results demonstrated that exposing chondrocytes to nsPEFs led to enhanced proliferation and dedifferentiation, evidenced by the upregulated gene expression of collagen type I (COL I) and downregulated gene expression of Sox9, collagen type II (COL II) and aggrecan (AGG) with activation of the wnt/β-catenin signaling pathway. Inhibition of the wnt/β-catenin pathway partially blocked these effects. Thus we concluded that nsPEFs induce dedifferentiation of chondrocytes partially through transient activation of the wnt/β-catenin signaling pathway.

“…Several studies reported necrosis due to the colloid-osmotic cell swelling as a predominant mechanism of cell death after exposure to nsEP5610212223. This mechanism could be blocked by isosmotic addition of a nanopore-impermeable solute (such as sucrose) to the growth medium32.…”

Section: Resultsmentioning

confidence: 99%

“…More recently, several groups including ours reported that cells exposed to nsEP swell and may die because of necrosis within the first several hours after the treatment5610212223. Necrosis is caused by the presence of long lived nanopores and colloid-osmotic imbalance which leads to cell swelling and membrane rupture.…”

mentioning

confidence: 81%

The cytotoxic synergy of nanosecond electric pulses and low temperature leads to apoptosis

Muratori

Pakhomov

Gianulis

et al. 2016

Electroporation by nanosecond electric pulses (nsEP) is an emerging modality for tumor ablation. Here we show the efficient induction of apoptosis even by a non-toxic nsEP exposure when it is followed by a 30-min chilling on ice. This chilling itself had no impact on the survival of U-937 or HPAF-II cells, but caused more than 75% lethality in nsEP-treated cells (300 ns, 1.8-7 kV/cm, 50-700 pulses). The cell death was largely delayed by 5-23 hr and was accompanied by a 5-fold activation of caspase 3/7 (compared to nsEP without chilling) and more than 60% cleavage of poly-ADP ribose polymerase (compared to less than 5% in controls or after nsEP or chilling applied separately). When nsEP caused a transient permeabilization of 83% of cells to propidium iodide, cells placed at 37 °C resealed in 10 min, whereas 60% of cells placed on ice remained propidium-permeable even in 30 min. The delayed membrane resealing caused cell swelling, which could be blocked by an isosmotic addition of a pore-impermeable solute (sucrose). However, the block of swelling did not prevent the delayed cell death by apoptosis. The potent enhancement of nsEP cytotoxicity by subsequent non-damaging chilling may find applications in tumor ablation therapies.